Trent on Why Mutations Matter for Patients With GIST

Jonathan C. Trent, MD, PhD

Better efficacy outcomes were observed among patients with advanced gastrointestinal stromal tumor (GIST) with circulating tumor (ct)DNA not detected compared with patients with GIST with ctDNA detected in both treatment arms of the open-label, phase 3 INTRIGUE study (NCT03673501).

In INTRIGUE, patients with advanced GIST who had disease progression on or intolerance to imatinib (Gleevec) were randomized in a 1:1 ratio and treated with either to ripretinib (Qinlock) 150 mg once daily (QD) or sunitinib (Sutent) 50 mg QD for 4 weeks on and 2 weeks off. Patients were also stratified by mutation according to a local pathology report.

A total of 362 patients were included in the trial, with 82 patients who were ctDNA not detectable (22.7%). Patients who were ctDNA not detectable were overall younger (median, 55.5 v 62.0 years) and had smaller sums of longest diameters of target lesions (median [range]: 57.6 [11-459] v 108.8 [15-418] mm).

According to findings presented at the 2023 ASCO Annual Meeting, patients with ctDNA not detectable had a longer progression-free survival (PFS) compared with patients who were ctDNA detectable. Patients with ctDNA not detectable who were categorized as not having a KIT exon 9 mutation at randomization (n = 71) also had a longer PFS with ripretinib vs sunitinib (median NE vs 11 months; HR, 0.56; 95% CI, 0.28-1.12). Additionally, the objective response rate (ORR) and overall survival (OS) were higher among patients with GIST with ctDNA not detectable vs ctDNA detectable, and safety data were similar between groups.

Overall, the median PFS was not different between treatment arms among patients with ctDNA not detectable and ctDNA detectable. These data suggest that for ripretinib or sunitinib treatment, ctDNA not detectable was not a predictor of response.

In an interview with Targeted Oncology^TM, Jonathan C. Trent, MD, PhD, professor and associate director for Clinical Research at Sylvester Comprehensive Cancer Center, University of Miami Health System, Miami, Florida, further discussed the INTRIGUE study, and provided some background on the GIST treatment landscape.

Targeted Oncology: What are the current just recommendations in terms of neoadjuvant and adjuvant treatments for patients with GIST?

Trent: Patients with primary GIST have a GIST that hasn't spread or metastasized to any organ. The most common organ is the liver followed by the peritoneal cavity. If you look at overall, all patients with a primary GIST who have surgery, there's about a 50% recurrence rate. In recent years, we've identified some predictive markers that predict a higher risk of recurrence, such as small intestine primary tumors larger than 10 centimeters and high-grade tumors in terms of mitotic rate greater than 10 per 50 high power fields. If you look at those high-risk features, some patients with GIST have virtually over 90% chance of their GIST coming back in the future with surgery alone.

A number of studies have looked at using imatinib, which is an anti-GIST tyrosine kinase inhibitor that attacks KIT mutations on the tumor in the setting of a primary tumor that's been resected. One of the early studies was the ACOSOG study [NCT00041197] that compared imatinib for 1 year vs no imatinib, and the patients did benefit if they took imatinib for 1 year with a decreased risk of their GIST coming back. Our group looked at 2 years of adjuvant imatinib, and we found that patients who had their primary tumor resected and took imatinib postoperatively for 2 years essentially had no chance of recurrence during that 2-year interval. They could recur subsequently.

Current studies performed in Europe have made the standard-of-care 3 years of imatinib after resection of a primary tumor in patients who are thought to have high-risk of recurrence. There is an ongoing study comparing 5 years to 3 years of imatinib for which we may have the answer in a few years. Neoadjuvant imatinib or taking imatinib prior to surgery for a primary GIST is often done in the setting of large tumors, complicated resections, or any situation where the patient would benefit from downstaging the surgery by making the patient's tumor smaller. A smaller tumor means less normal tissue has to be removed, so we try to do that in those settings and use preoperative imatinib in that context.

Then in our center, we include the duration of preoperative imatinib in the overall treatment postoperatively so that if the patient takes 6 months preoperative imatinib, we would give them 30 months of postoperative imatinib to have a total of the 3 years, which is the standard-of-care today.

What are the recommendations for the treatment of frontline GIST? How about second-line GIST?

The standard recommendation for frontline GIST in the metastatic setting is the use of imatinib. Imatinib was studied in a clinical trial in the early 2000s and is still standard-of-care today as frontline initial therapy for metastatic GIST. When patients progress on imatinib, the recommendations get a little murky. Standard therapy based on the clinical trial with sunitinib vs placebo that was performed in the second-line setting suggests that sunitinib should be standard second-line therapy for all patients whose tumors progress on imatinib. Now, there's emerging data that circulating tumor DNA may influence that decision in the future. Our center looked at circulating tumor DNA in patients with GIST whose tumors were progressing on imatinib or beyond and found that about a third have KIT exon 13 resistance mutations, and about 2 thirds have KIT exon 17 resistance mutations.

There's emerging data from some prospective clinical trials from our retrospective series and laboratory data that KIT exon 13-mutated resistance GIST is most sensitive to sunitinib and relatively resistant to other TKIs. On the other hand, KIT exon 17-mutated resistant GIST seems to be much more sensitive to other TKIs, such as ripretinib and regorafenib than sunitinib. That's laying the groundwork of the possibility that perhaps we should be performing circulating tumor DNA and all of our resistant patients and treating them with the optimal therapy that gives them the best chance of response to the agent. Excitingly, there are 2 prospective clinical trials testing this concept. There's 1 trial for patients with KIT exon 17-resistant GIST that are being randomized to either sunitinib or ripretinib. Then, there's our prospective trial at our site where patients with resistant GIST have ctDNA performed. If they have exon 13, they're treated with sunitinib, and if they have exon 17, they're treated with ripretinib in a prospective fashion. I think these 2 studies will tell us whether using ctDNA guided therapy improves patient outcomes.

Can you explain the methods and design of the INTRIGUE study?

The INTRIGUE study was designed for patients with imatinib-resistant GIST. These patients were treated in the second-line of the study. Patients were randomized to either sunitinib or ripretinib in an open-label design with a 1 to 1 randomization and then followed for adverse events, followed for several efficacy parameters, and then allowed to cross over at the time of progression.

What were the findings from the study?

Unfortunately, the study did not mean the end point of favorability for ripretinib. At this point in time, we can't say that ripretinib is any better than sunitinib in second-line GIST. We did notice that the tolerability of ripretinib seemed to be slightly better. Now ripretinib is in our National Cancer Center Network or NCCN guidelines for second-line therapy for patients who may not tolerate sunitinib.

What are the key takeaways from this trial?

At ASCO this year, there were several publications looking at molecular subsets of patients from the INTRIGUE study. Those subsets included patients with exon 17 or 18 resistance mutations, but also our study that looked at circulating tumor DNA in patients on the INTRIGUE study who were randomized to ripretinib or sunitinib. We asked the question of whether circulating tumor DNA could be a biomarker for patient outcomes. We looked at whether circulating tumor DNA was detected in about 77% of patients, or not detected in about 23% of patients. We homed in on those 23% of patients that did not have any circulating tumor DNA detected. We looked at their outcomes and we found that their progression-free survival, and their overall survival were statistically better than patients who had their circulating tumor DNA detected.

In fact, at the time of this analysis, the overall survival had not even been reached yet for the patients without detectable circulating tumor DNA, whereas the patients that had the detectable circulating tumor DNA had a median overall survival of 28 months. So, who are these patients? We looked in a little more detail and we found that they tended to be younger patients, about 10 years younger, on average, and they were the patients without detectable circulating tumor DNA. It does seem to be providing a biomarker.

We also looked at whether ctDNA detectability predicted response to reprinting vs sunitinib. Essentially, we found that there was no statistically significant difference which we take to mean that patients with circulating tumor DNA not detected can benefit equally from ripretinib and sunitinib. It shouldn't be a deterrent to treatment, but it is a favorable biomarker so that maybe you don't have to rush into the next line of therapy.

For a community oncologist, what are the key recommendations moving forward?

The key recommendations from the abstracts at ASCO this year, and for the last probably 15 years, is that patients with GIST are going to be treated with a tyrosine kinase inhibitor, must have mutation testing performed, whether that's from the original tumor surgery or biopsy block, or whether that circulating tumor DNA. You can't optimally treat a patient with GIST unless you know what specific mutation they have. The mutation could be a KIT or PDGFRA, which we may treat with imatinib. However, there's a PDGFRA D842V-mutant that is resistant to everything except avapritinib [Ayvakit]. That patient would have to be treated with avapritinib.

Then there's also RAF and there's TRK and these won't benefit from the KIT-directed therapies such as imatinib. RAF-mutant you need to treat with a RAF inhibitor, and TRK should be treated with larotrectinib [Vitrakvi] or entrectinib [Rozlytrek]. Honestly, the mutation matters, and you have to do mutation testing on patients if you're going to treat them.

Trent, JC, Jones RL, George S, et al. Outcomes in patients with advanced gastrointestinal stromal tumor who did not have baseline ctDNA detected in the INTRIGUE study. J Clin Oncol. 2023;41(suppl 16):11536. doi:10.1200/JCO.2023.41.16_suppl.11536